Category Archives: C. difficile Treatment Clinical Studies

The Australian biopharmaceutical company Immuron announced that the first patients have enrolled in phase 1/2 (first-in-human) clinical trials for Immuron’s IMM-529, an oral immunotherapeutic medication for treatment of Clostridium difficile infections (CDI).

As published in MD Mag February 16, 2018

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According to Dan Peres, MD, senior vice president and head of medical development at Immuron, IMM-529 “has shown promise in successfully treating Clostridium-difficile” through its “unique delivery of antibodies.”

If the trials are successful, IMM-529 may be a powerful new weapon in the global fight against CDI. Peres reports that IMM-529 that has been effective in preclinical studies for prophylactic use, treatment of disease, and the prevention of recurrence in relation to CDI, and that the company is excited to enroll the first patients.

The placebo-controlled study to test the safety, tolerability and efficacy of IMM-529 will take place at Hadassah Medical Center in Jerusalem and include 60 CDI diagnosed patients in the 28 day study.

Patients enrolled in the study, led by Yoseph Caraco, MD, head of the clinical pharmacology unit at Hadassah Medical Center, will receive IMM-529 or a placebo 3 times a day during the 28 -day trial period, and be monitored for 2 additional months, determining any recurrence of the disease.

In a statement, Caraco said that he was optimistic about IMM-529 based on pre-clinical trial results and that IMM-529 could “be the answer we’re all looking for” when it comes to treatment of CDI.

IMM-529 targets CDI in 2 ways: by neutralizing toxin B (TcdB), a cytotoxin responsible for inflammation and diarrhea that characterizes CDI, and by binding Clostridium difficile spores and vegetative cells preventing further colonization. Caraco reported that IMM-529 approaches CDI by “targeting the main virulence factors of the disease with only minor disturbance to the natural biome” which could be extremely valuable in treating CDI.

In the earlier pre-clinical proof-of-concept study by led by Dena Lyras, MD, PhD with Monash University in Melbourne, Australia, IMM-529 was shown to be 80% effective in both the treatment of and prevention of CDI without the use of antibiotics.

In a December 2015 statement from Immuron, Lyras stated that she was “excited by the potential of these therapeutics in treating patients with both the acute and the relapse phase, of the disease.”

According to data supplied by the American Gastroenterological Association, approximately 500,000 people in the US are diagnosed with CDI each year, and CDI-associated deaths range from 14,000 to 30,000 per year.

In the European Union, according to a 2016 study led by Alessandro Cassini, MD, with the European Centre for Disease Prevention and Control in Stockholm, Sweden, more than 150,000 cases of hospital-acquired CDI infections (134,053–173,089; 95% CI) occur each year.

According to Immuron, the cost of CDI globally (calculated by CIDRAP, the Center for Infectious Disease and Policy at the University of Minnesota) is an estimated annual economic burden of more than $10 billion and increases in hypervirulent and antibiotic-resistant strains have led to CDI becoming a major medical concern.

Caraco stated that CDI poses “a growing risk amongst a greater population of patients, including those recently treated with antibiotics, the elderly, institutionalized and hospitalized.”

If IMM-529 is found to be safe and effective in clinical trials, it could prove a significant boon to the global fight against CDI at all 3 stages of the disease.

In a randomized, controlled, open label phase 3b/4 trial (ClinicalTrials.gov identifier: NCT02254967), hospitalized patients age 60 years and older with confirmed C difficile infection were recruited from 86 European hospitals. Patients were randomly assigned to receive extended-pulsed fidaxomicin (200-mg oral tablets, twice daily on days 1–5, then once daily on alternate days on days 7-25) or vancomycin (125-mg oral capsules, 4 times daily on days 1-10).

Multivariate analysis, which included treatment arm and baseline stratification factors (infection severity, cancer presence, age, and number of previous C difficile infection occurrences) as covariates, also indicated fidaxomicin to be superior (P =.035). A subanalysis of microbiota diversity concluded that microbiota recovery was greater in the fidaxomicin group, and a Cox proportional hazards model suggested that the hazard of infection recurrence in the vancomycin group was 3.8 times greater.

This study demonstrates the superiority of extended-pulsed fidaxomicin treatment over standard treatment with vancomycin. The researchers note the absence of blinding and racial diversity in the study group as limitations and recommend that future investigations should study this treatment course in patients age 60 years and younger and should compare this treatment course with standard fidaxomicin treatment protocols.

Disclosure

The study was funded by Astellas Pharma Inc, who were involved in all stages of the study, including manuscript preparation.

In the USA: Nearly half a million Americans suffer from Clostridium difficile (C. diff.) infections in a single year according to a study released in 2015 by the Centers for Disease Control and Prevention (CDC). Approximately 29,000 patients died within 30 days of the initial diagnosis of C. difficile. Of those, about 15,000 deaths were estimated to be directly attributable to C. difficile infections making C. difficile a very important cause of infectious disease death in the United States.

“Clostridium difficile infections are not only the most common cause of healthcare-acquired infections in the United States but also very common in the community in younger patients who previously were thought to be less susceptible to C. difficile. The rate of recurrent C. difficile infections is increasing tremendously and this increase is higher than the rate of primary C. difficile infections,” stated Sahil Khanna, MD, Assistant Professor of Medicine Division of Gastroenterology and Hepatology, Director of the C. difficile Clinic, Fecal Microbiota Transplantation program and C. difficile related Clinical Trials, Mayo Clinic, Rochester, MN.

Dr. Khanna also added, “It is imperative and important for clinical trials to be done to advance the development of new treatments, new medications, and new ways to prevent and treat Clostridium difficile infections.”

Individuals volunteer to participate in clinical trials in hopes of improving their own health, to access treatments that might not be available otherwise, often because they are new and not yet widely available. They help others by contributing to advances in medicine. There can also be potential risks participating in clinical trials and clinical studies. All of the known risks associated with a particular trial and or study will be discussed during the informed consent process. It will be thoroughly explained in the informed consent document that a volunteer will receive from the research staff prior to participating in any study.

To learn more about clinical research (e.g., Clostridium difficile, C.difficile) visit the U.S. Food and Drug Administration http://www.fda.gov or telephone 1-800-835-4709, The National Institutes of Health (NIH) http://www.nih.gov and ClinicalTrials.gov.

“Clinical trials are vital to improving our knowledge about how best to prevent and treat C. difficile infections. Informing patients of clinical trials is important, and in recent years several clinical trials have led to significant improvements in the treatments available for patients with C. difficile infections,” stated Mark Wilcox, MD, FRCPath, Consultant Microbiologist, Head of Microbiology and Academic Lead of Pathology Leeds Teaching Hospitals, Professor of Medical Microbiology University of Leeds Institute of Biomedical and Clinical Sciences, Lead on Clostridium difficile for Public Health England, UK.

About the U.S. Food and Drug Administration (FDA):
The FDA is responsible for protecting the public health by assuring that foods are safe, wholesome, sanitary and properly labeled; ensuring that human and veterinary drug, and vaccines and other biological products and medical devices intended for human use are safe and effective. FDA’s responsibilities extend to the 50 United States, the District of Columbia, Puerto Rico, Guam, the Virgin Islands, American Samoa, and other U.S. territories and possessions.

About the National Institutes of Health (NIH):
The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the nation’s medical research agency making important discoveries that improve health and save lives.

About ClinicalTrials.gov
ClinicalTrials.gov is a Web-based resource that provides patients, their family members, health care professionals, researchers, and the public with easy access to information on publicly and privately supported clinical studies on a wide range of diseases and conditions.

Summit Therapeutics — the drug discovery and development company advancing therapies for Duchenne muscular dystrophy and Clostridium difficile infection (‘CDI’), announces that it has entered into an exclusive license and commercialization agreement granting Eurofarma Laboratórios SA (‘Eurofarma’) rights in Latin America (the ‘Licensed Territory’) to Summit’s precision antibiotic ridinilazole in development for the treatment of CDI.

Summit retains commercialization rights in all other countries.

ridinilazole is a targeted antibiotic that has the potential as a frontline therapy to treat initial infection and preserve patients’ microbiomes to reduce the rate of recurrent CDI. In a Phase 2 proof of concept trial in CDI patients, ridinilazole demonstrated statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin.

ridinilazole is expected to enter Phase 3 clinical trials in the first half of 2018.

“Eurofarma’s established infrastructure and expertise in Latin America are ideally placed to commercialise our novel antibiotic, ridinilazole,”commented Glyn Edwards, Chief Executive Officer of Summit. “This agreement, combined with the recent contract award of up to $62 million from the US Government agency BARDA, will further support the Phase 3 clinical programme and regulatory development of ridinilazole. These partnerships endorse the potential of ridinilazole in the treatment of CDI, and move us a step closer to bringing this antibiotic to patients.”

Eurofarma is a multinational pharmaceutical company with headquarters in Brazil and operations in over 20 countries in South and Central America, the Caribbean and Africa. Eurofarma has a broad portfolio of products across multiple therapeutic areas including a focus in infectious diseases where it markets a number of antibiotics.

“CDI is a serious global healthcare threat including in Latin America,” added Martha Penna, P&D Vice-president of Eurofarma. “Through our interest in bringing innovative products to the region, we were impressed by the efficacy data from the ridinilazole Phase 2 programme and the differentiated profile of the drug. We believe it has the potential to address a major unmet need in CDI, and we look forward to working with Summit to bring ridinilazole to market for the benefit of patients.”

Under the terms of the licence and commercialisation agreement, Summit will receive an upfront payment of $2.5 million, and is entitled to receive a further $3.75 million in development milestones upon the achievement of staged patient enrolment targets in the planned Phase 3 clinical trials of ridinilazole. Summit is eligible to receive up to an additional $21.4 million through other development milestones, commercial milestones, and one-time sales milestones based on cumulative net sales up to $100 million in the Licensed Territory. Further, the agreement provides for product supply transfer payments expected to provide a return equivalent to a high single digit to low double-digit percentage of net sales. For each incremental $100 million in cumulative net sales achieved, Summit is entitled to a further milestone payment which, when combined with the aforementioned product supply transfer payments, is expected to provide a return equivalent to a mid- to high-teens percentage of net sales.

Eurofarma will be responsible for obtaining regulatory approval for ridinilazole in the Licensed Territory. Summit retains full responsibility for the clinical development of ridinilazole in all countries, and is responsible for obtaining regulatory approvals outside of the Eurofarma licensed territories.

A Form 6-K will be filed with the US Securities and Exchange Commission (‘SEC’) that contains additional information about the terms of the licence and commercialisation agreement with Eurofarma.

A copy of this Form 6-K will be available to download either from the Investors section of the Company website at www.summitplc.com or from the SEC website at www.sec.gov.

This announcement contains inside information for the purposes of Article 7 of EU Regulation 596/2014 (MAR).

About Ridinilazole

Ridinilazole is a small molecule precision antibiotic that Summit is developing for the treatment of CDI. In preclinical efficacy studies, ridinilazole exhibited a targeted spectrum of activity that combined a potent bactericidal effect against all clinical isolates of C. difficile tested with minimal impact on other bacteria that are typically found in the gut microbiome. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin. In that trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy. Ridinilazole was also shown to be highly preserving of the gut microbiome in the Phase 2 proof of concept trial, which was believed to be the reason for the improved clinical outcome for the ridinilazole-treated patients. In addition, ridinilazole preserved the gut microbiome to a greater extent than the marketed narrow-spectrum antibiotic fidaxomicin in an exploratory Phase 2 clinical trial. Ridinilazole, an orally administered small molecule, has received Qualified Infectious Disease Product (‘QIDP’) designation and has been granted Fast Track designation by the US Food and Drug Administration. The QIDP incentives are provided through the US GAIN Act and include an extension of marketing exclusivity for an additional five years upon FDA approval.

About Summit Therapeutics

Summit is a biopharmaceutical company focused on the discovery, development and commercialisation of novel medicines for indications for which there are no existing or only inadequate therapies. Summit is conducting clinical programmes focused on the genetic disease Duchenne muscular dystrophy and the infectious disease C. difficile infection. Further information is available at www.summitplc.com and Summit can be followed on Twitter (@summitplc).

About the Eurofarma Group

As the first 100% Brazilian-owned multinational pharmaceutical company, Eurofarma has been in existence for 45 years, has 6,500 employees, and has operations in 20 Latin American countries. With 12 manufacturing plants in the region, the company has more than 280 products in its portfolio. In 2016, it produced more than 290 million units and reached revenues of R$3.3 billion, 15.7% higher than the previous year. The Group invests approximately 5.5% of its net sales in Research & Development and maintains a pipeline of more than 175 projects.

About Eurofarma Brazil

Considered one of the best companies to work for, Eurofarma Brazil is also considered the most sustainable pharmaceutical company in the country based on an analysis by the Exame Sustainability Guide. With operations in all main pharmaceutical segments including Medical Prescriptions, Generics, Hospital, Oncology, Veterinary, and Bids and Services to Third Parties, Eurofarma has the largest medical advertising salesforce in Brazil with more than 2,000 representatives that together perform 450,000 medical contacts per month. The company has the 4th largest pharmacy system in the country and has a portfolio of medicines that is the 2nd largest by prescription volume.

Additional cohorts to examine potential of reduced dosing regimens of RBX7455 for the prevention of recurrent Clostridium difficile infection

Rebiotix Inc., a clinical-stage microbiome company
focused on harnessing the power of the human microbiome to treat challenging diseases, announced on November 30, 2017
an expansion of the investigator sponsored Phase 1 study of RBX7455 for the prevention of recurrent Clostridium difficile (C. diff.) infection. The expansion follows the successful completion of the study’s two initial cohorts and is intended to explore reduced dosing regimens of RBX7455 in two new treatment arms. RBX7455 is a lyophilized, non-frozen oral capsule formulation of Rebiotix’s Microbiota Restoration Therapy™ (MRT), a standardized, stabilized drug technology that is designed to rehabilitate the human microbiome by delivering a broad spectrum of live microbes into a patient’s intestinal tract via a ready-to-use and easy-to-administer format.

“Expansion of the Phase 1 study is a key advancement in the development of RBX7455 as it provides an opportunity to explore the potential efficacy of reduced dosing regimens of our oral capsule product in the prevention of recurrent C. diff. infection,” stated Lee Jones, president and CEO of Rebiotix. “RBX7455 is a ground-breaking product in that its oral capsule design is the first in the microbiome industry not requiring storage in frozen conditions. As such, patients are able to administer RBX7455 at home as they would a typical oral capsule medication, which potentially makes RBX7455 ideally suited for diseases where chronic or repeat dosing is required.”

The Phase 1 study of RBX7455 is an investigator sponsored, prospective, single center, proof of concept dosing study of RBX7455 for the prevention of recurrent C. diff. infection. The first two arms enrolled 10 patients per arm (20 total). The expansion of the Phase 1 study adds two additional arms, which will enroll approximately 10 patients per arm (20 total) with reduced dosing regimens from the 2
first two arms. Rebiotix expects data from the first two cohorts of the Phase 1 study of RBX7455 to be released publicly by mid-2018.

In addition to the expanded Phase 1 study of RBX7455, Rebiotix’s clinical development pipeline is highlighted by the company’s ongoing Phase 3 clinical trial of RBX2660 for the prevention of recurrent C. diff. infection. RBX2660 is the first and only microbiome drug to be tested in three separate Phase 2 trials, with more than 300 subjects having been treated with the microbial therapy.

Recently, Rebiotix announced the presentation of research from the RBX2660 Phase 2 program demonstrating measurable evidence of the drug’s rehabilitative effect on the human microbiome and the potential advantages of its broad consortia design.
Ms. Jones continued, “We look forward to the continued progress of the RBX7455 Phase 1 study as well as our Phase 3 study of RBX2660, our lead microbiome drug candidate. Importantly, since both drugs were developed with our MRT platform, we can leverage knowledge from the extensive RBX2660 clinical program, as well as research into the drug’s rehabilitative impact on the gut microbiome, to inform and expedite the development of RBX7455.”

About Rebiotix Inc.
Rebiotix Inc. is a late-stage clinical microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of challenging diseases. Rebiotix possesses a deep and diverse clinical pipeline, with its lead drug candidate, RBX2660, in Phase 3 clinical development for the prevention of recurrent Clostridium difficile (C. diff.) infection. RBX2660 has been granted Fast Track status, Orphan Drug and Breakthrough Therapy designation from the FDA for its potential to prevent recurrent C. diff. infection.

Rebiotix’s clinical pipeline also features RBX7455, a lyophilized nonfrozen,
oral capsule formulation, which is currently the subject of an investigator-sponsored Phase 1 trial for the prevention of recurrent C. diff. infection. In addition, Rebiotix is targeting several other disease states with drug products built on its pioneering Microbiota Restoration TherapyTM (MRT) platform.

MRT is a standardized, stabilized drug technology that is designed to rehabilitate the human microbiome by delivering a broad consortium of live microbes into a patient’s intestinal tract via a ready – to-use and easy-to-administer format. For more information on Rebiotix and its pipeline of human microbiome-directed therapies, visit www.rebiotix.com

He said Mayo Clinic is also studying whether or not there could be a vaccination for C. Diff.

“So there’s a large multi-center study that’s going on right now in people who may be at risk for C. Diff infection,” Khanna said. “So if you’ve been to the hospital, if you’ve received antibiotics, those patients can be enrolled in a vaccine study to see if this vaccine would prevent C. Diff from happening.”

Mayo Clinic is also working with Minnesota-based company Rebiotix on another form of treatment for the infection where people can simply ingest a tablet.

“Newer studies are being derived where you can actually take material from donor stool, process donor stool in a lab, and derive all the good bacteria that you need from the donor stool and put them in capsule form,” Khanna said.

Khanna said this capsule-based treatment has more advantages than a colonoscopy-based treatment that is currently being used to treat C. Diff.

A similar proportion of patients with Clostridium difficile infection showed clinical response at the end of treatment with surotomycin vs. vancomycin in a pivotal phase 3 trial.

However, surotomycin did not demonstrate superiority for key secondary endpoints including sustained clinical response and clinical response over time, and therefore failed to show benefit over vancomycin.

“Surotomycin has a narrow spectrum of activity, demonstrating low resistance rates and rapid activity against C. difficile with similar dose- and time-dependent pharmacodynamics to vancomycin in resolving CDI in a hamster model,” Sahil Khanna, MBBS, of the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn., told Healio Gastroenterology and Liver Disease.

In this second phase 3 trial, “surotomycin demonstrated non-inferiority to vancomycin for CDI clinical response at end of treatment. It was similar to vancomycin for sustained clinical cure.”

At the end of treatment, clinical response with surotomycin (83.4%) was non-inferior to vancomycin (82.1%), with a difference of 1.4% (95% CI, 4.9-7.6).

Through 30 to 40 days of follow-up, clinical response over time was not superior to surotomycin, nor was sustained clinical response (63.3% vs. 59%; difference, 4.3%; 95% CI, 3.6-12.2).

Both treatments were generally well tolerated, with typical treatment-emergent adverse events occurring in 52.4% of patients treated with surotomycin and 60.1% of those treated with vancomycin.

“Interestingly, in the hypervirulent strain of CDI, recurrence rate was lower for surotomycin vs. vancomycin,” Khanna said, though he and colleagues noted in the study manuscript that “this finding is nominal due to a lack of multiplicity control.”

Based on the results of these trials, the surotomycin development program has been discontinued, but “the non-inferiority of surotomycin to vancomycin observed in the current trial is in contrast with the parallel trial,” investigators wrote. – by Adam Leitenberger

Disclosures: This study was funded by Merck. Khanna reports he has served as an advisor to Summit Pharmaceuticals and serves as a consultant to Rebiotix and Assembly Biosciences. Please see the full study for a list of all other researchers’ relevant financial disclosures.

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